Platelet Activating Factor (PAF), 1-O-hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine, is an ether lipid produced by a variety of different cell types. Recent studies [Snyder, F., Ann. Rep. Med. Chem., 17,243 (1982); Pinckard, R. N., et. al., J. Adv. Inflammation Res., A, 147 (1982); O'Flaherty, J. T., et. al., Clin. Rev. Allergy, 1, 353 (1983); Vargaftig, B. B., et. al., J. Trends. Pharmacol. Sci., A, 341 (1983)] have shown PAF to be an important mediator of allergic disease. When injected into mammals, PAF induces hemodynamic and hematological changes including hypotension, platelet aggregation, neutropenia, disseminated intravascular coagulation, increases in vascular permeability, bronchoconstriction, tissue injury (hypoxia and necrosis) and eventually death (reviewed by Cammussi, G. Kidney Int. 29, 469, (1986). In recent years, it has been postulated that PAF is the mediator of tissue injury in mammals undergoing endotoxic shock due to bacterial sepsis (Terashita, Z., Y. Imura, K. Nishikawa and S. Sumida 1985, Eur. J. Pharmacol. 109:257-261; Doebber, T. W., M. S. Wu, J. C. Robbins, B. M. Choy, M. N. Chang and T. Y. Shen 1985, Biochem. Biophys. Res. Comm. 127:799-808; Inarrea, P., Gomez-Cambronero, J. Pascual, M. del Carmen Ponte, L. Hernando and M. Sanchez-Crespo. 1985, Immunopharmacology, 9:45-52). These studies, in mammals, have shown that PAF is produced in large amounts when the said mammal has been treated with endotoxin. In addition, mammals undergoing endotoxic shock exhibit all of the clinical symptoms associated with the administration of PAF. In addition, PAF is implicated in asthma, respiratory distress syndrome, lung edema and other inflammatory and cardiovascular diseases.
The compounds of the present invention have proven to be specific inhibitors of the biological fects of PAF and are consequently useful for the treatment of asthma, anaphylactic and septic (endotoxic) shock, psoriasis, bowel necrosis, adult respiratory distress syndrome, transplant rejection, thrombosis, stroke, cardiac anaphylaxis and cancer.
Concurrently, with the realization that PAF is an important mediator of inflammatory diseases in mammals, a number of structurally different antagonists of PAF have been developed. References to some of these antagonists are listed hereinbelow.
Terashita, Z.; Imura, Y. Takatani, M. Tsushima, S.; Nishikawa, K., J. Pharmacol. Exp. Ther., 1987, 242, 263-268. PA0 Takatani, M.; Yoshioka, Y.; Tasaka, A.; Terashita, Z.-I.; J. Med. Chem., 1989, 32, 56-64. PA0 Tsushima, S.; Takatani, M.; Kohei, N. Eur. Patent Appln. EP 301751 (Feb. 1, 1989). PA0 Tomesch, J. C. U.S. Pat. No. 4,820,718 (Apr. 11, 1989). PA0 Gustafson, A.; Handley, D. A.; Tomesch, J. C.; Prashad, M. FASEB J, 1989, 3, A1224. PA0 Page, C.; Abbott, A. TIPS, July 1989, 10, 1. PA0 U.S. Pat. No. 4,916,145 (Oct. 4, 1990). PA0 European Patent Appln. EP 327,962 (Aug. 16, 1989). PA0 European Patent Appln. EP 301,751 (Feb. 1, 1989). PA0 European Patent Appln. EP 353,474 (Feb. 7, 1990). PA0 Spanish Patent Appln. ES 2,010,937 (Dec. 1, 1989). PA0 Spanish Patent Appln. ES 2,010,932 (Dec. 1, 1989). PA0 European Patent Appln. EP 353,777 (Feb. 7, 1990). PA0 U.S. Pat. No. 4,820,718 (Nov. 4, 1989).
BRIEF SUMMARY OF THE INVENTION
The compounds of the present invention are represented by the formula: ##STR1## wherein:
(A) X is a divalent radical selected from the group consisting of: ##STR2## wherein Y is a divalent radical selected from the group represented by OCH.sub.2, (CH.sub.2).sub.n, (CH.sub.2).sub.n+1 O; p is the integer 0, 1, 2, or 3; n is the integer 0, 1, or 2; R.sub.4 is selected from the group consisting of hydrogen, phenyl, --COR.sub.6 or --SO.sub.2 R.sub.7 ; wherein R.sub.6 is selected from C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkenyl, C.sub.1 -C.sub.6 alkylamino, C.sub.1 -C.sub.6 alkoxy, phenyl, aminophenyl, substituted phenyl and substituted aminophenyl and the substituents are selected from the group consisting of one or more of the following C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, halogen and trifluoromethyl; R.sub.7 is selected from the group of C.sub.1 -C.sub.25 alkyl, C.sub.1 -C25 alkenyl, phenyl and substituted phenol and the substituents are selected from the group consisting of C.sub.1 -C.sub.20 alkyl, C.sub.1 -C.sub.20 alkoxy, halogen and trifluoromethyl; R.sub.5 is selected from the group consisting of --COR.sub.6 and --SO.sub.2 R.sub.7 wherein R.sub.6 and R.sub.7 are as previously described above with the proviso that when ##STR3## and Y is (CH.sub.2).sub.n with n=0, R.sub.4 cannot be hydrogen or phenyl;
(B) R.sub.1 represents one or more substituents of the aromatic ring which may be the same or different and is selected from the group consisting of:
(i) C.sub.1 -C.sub.25 alkyl, C.sub.1 -C.sub.25 alkenyl, C.sub.1 -C.sub.25 alkoxy, C.sub.1 -C.sub.25 alkenyloxy, C.sub.1 -C.sub.25 thioalkyl, phenyl, phenoxy, substituted phenyl, and substituted phenoxy wherein the substituents are selected from the group consisting of C.sub.1 -C.sub.20 alkyl, C.sub.1 -C.sub.20 alkoxy, halogen, and trifluoromethyl; PA1 (ii) halogen, trifluoromethyl, cyano, and nitro; PA1 (iii) --CO.sub.2 R.sub.7, --CONHR.sub.7, --OCONHR.sub.7, and --NHCOR.sub.7 wherein R.sub.7 is as previously described above;
(C) the moiety R.sub.2 represents one or more substituents of the pyridine ring which may be in any position and are selected from the group consisting of hydrogen, C.sub.1 -C.sub.5 alkyl, C.sub.1 -C.sub.5 alkoxy, and halogen;
(D) the heterocycle is bonded to the X-group at optionally the 2, 3, or 4 position;
(E) the group R.sub.3 is selected from the group consisting of C.sub.1 -C.sub.8 alkyl, C.sub.1 -C.sub.8 halogen (bromine, chlorine or fluorine) substituted alkyl, benzyl, hydrogen or N-oxide; Z.sup..crclbar. represents a pharmacologically acceptable anion.